Project Summary Abuse of prescription opioids and fatalities related to their misuse have increased sharply in recent years, making the development of pain medications with reduced abuse potential a major public health priority. When combined, opioids and cannabinoid (CB) receptor agonists show analgesic effects appear to be at least additive in a number of pain models. Cannabidiol (CBD), although much less psychoactive than ?9-tetrahydrocannabinol (THC), the primary active principle in Cannabis, still retains analgesic effects. Efforts to develop analogs of CBD with improved solubility and bioavailability resulted in discovery of CBD-valinate-hemisuccinate (CBD-VHS), which gives excellent performance in its own right in pain models, but also reduces the rewarding effects of morphine in a conditioned place preference test. The next steps, addressed in this project, are to carefully delineate the effects of CBD-VHS in combination with the commonly-used opioid therapeutic oxycodone, in order to understand their analgesic interactions and the abuse liability of the combinations. This will be done by using drug self-administration tests and analgesia models to find out whether mixture ratios that are less reinforcing still produce good pain relief. These goals will be achieved by first giving oxycodone (OXY) by the intravenous route, establishing dose-responses to OXY alone, then giving CBD-VHS in various doses and see how this affects responses to OXY. Once appropriate dose ratios are selected, then the combination will be evaluated for its ability to relieve pain. Validated isobolographic and dose-addition analyses will be used to determine if the combinations are additive or interactive (i.e., supra- or infra-additive) in analgesic effect. The outcome of this Phase I effort will be the selection of the most promising fixed ratio of oxycodone and CBD-VHS formulation for further preclinical development in the phase II STTR, as a pain management therapeutic with minimized abuse liability. The Phase II development program will include characterization of the interaction in nonhuman primates, pharmacokinetic and pharmacological assessments from oral formulations, and safety evaluations.